Wilms Tumor Suppressor, WT1, Cooperates with MicroRNA-26a and MicroRNA-101 to Suppress Translation of the Polycomb Protein, EZH2, in Mesenchymal Stem Cells

Abstract

Hereditary forms of Wilms arise from developmentally arrested clones of renal progenitor cells with biallelic mutations of WT1; recently, it has been found that Wilms tumors may also be associated with biallelic mutations in DICER1 or DROSHA, crucial for miRNA biogenesis. We have previously shown that a critical role for WT1 during normal nephrogenesis is to suppress transcription of the Polycomb group protein, EZH2, thereby de-repressing genes in the differentiation cascade. Here we show that WT1 also suppresses translation of EZH2. All major WT1 isoforms induce an array of miRNAs, which target the 3 UTR of EZH2 and other Polycomb-associated transcripts. We show that the WT1(؉KTS) isoform binds to the 5 UTR of EZH2 and interacts directly with the miRNA-containing RISC to enhance post-transcriptional inhibition. These observations suggest a novel mechanism through which WT1 regulates the transition from resting stem cell to activated progenitor cell during nephrogenesis. Our findings also offer a plausible explanation for the fact that Wilms tumors can arise either from loss of WT1 or loss of miRNA processing enzymes.In 1879, William Osler reported two pediatric patients from Montreal with massive kidney tumors containing bands of muscle-like tissue mixed with epithelial elements (35). Twenty years later, Max Wilms published his celebrated monograph recognizing the malignancy as a unique "mischgeschwulste der Niere" (mixed tumor of the kidney), composed of mixed stromal, epithelial, and undifferentiated mesenchymal cells. This "triphasic" histology suggests that Wilms tumors arise from developmentally arrested stem cells of the metanephric mesenchyme that occasionally exhibit abortive differentiation toward a stromal or an epithelial cell fate. It follows that a disturbance of molecular events governing the transition from renal progenitor cells into these differentiated lineages must be central to the pathogenesis of Wilms tumor. Wilms tumor (WT)2 is the most common form of pediatric kidney cancer and affects about 1:10,000 children in North America (1). In a subset of these patients, a germline deletion of the transcription factor, WT1, is accompanied by a somatic mutation of the second WT1 allele, giving rise to clones of incompetent stem cells adjacent to the malignant tumor (2). These "nephrogenic rests" are thought to represent embryonic renal progenitors that have failed to respond to inductive WNT signals during embryogenesis. The pre-malignant cell clusters may persist within the normal kidney (3) until a constitutively activating mutation of the ␤-catenin gene (CTNNB1) (17, 18) bypasses the need for a normal WNT signal and drives un-regulated rapid cell growth (4). Wilms tumors retain a chromatin pattern resembling embryonic stem cells in which genes of the differentiation cascade are broadly silenced by tri-methylated lysine 27 residues in the H3 histone associated with their promoter regions (5). We recently showed that the WT1 isoforms lacking the three amino acid insertion lysine-threonine-serine b...

Tumour suppressor WT1 regulates the let-7-Igf1r axis in kidney mesenchyme

“…3B). It has been previously shown that WT1 interacts with the microRNA pathway components DICER and AGO2 (Akpa et al, 2016). WT1 interaction with AGO1 and AGO2 was confirmed in the mesonephric cells ( Fig.…”

Structure of WT1 zinc fingers bound to its cognate DNA: Implications of the KTS insert

“…Mutations in WT1 gene have been implicated in abnormal development of the genito-urinary system resulting in syndromes such as Wilm's Tumor, Denys-Drash, WAGR and Frasier [4][5][6][7][8]. Recent studies however suggest an even wider spectrum of functions for WT1, including epigenetic regulation of genes [9][10][11][12], stem cell differentiation [13] and genome stability [14,15].…”

MiR-30a-5p promotes cholangiocarcinoma cell proliferation through targeting SOCS3

“…Collectively, these data suggested that miR-30a-5p could be a potential therapeutic target of CCA. miR-30a-5p, as a member of the mir-30 family, plays a crucial role in tumor growth and metastasis [5,6]. Currently, the expression profile and function of miR-30a-5p in different malignancies are still existed controversies.…”

“…More evidence showed that the dysfunction or abnormal expression of miRNAs maybe lead to incidence of human malignancies, and play important roles in tumor growth and metastasis [5,6]. Furthermore, miRNAs can as the biomarker of the diagnosis and as potential cancer therapeutics [7,8].…”